The present invention, in some embodiments thereof, relates to behavioral phenotyping and, more particularly, but not exclusively, to a method and apparatus for automatically classifying behavioral phenotypes and/or reactions to treatments in model organisms, for example, from single to multiple socially interacting individuals.
Laboratory mice, rats, fish and many other organisms display many genetic and behavioral characteristics which resemble that of humans. This makes them suitable candidates for testing and for evaluating the effects of drugs and other treatments being developed for humans. In particular, mice and humans share many behavioral characteristics such as, for example, anxiety, aggression, circadian rhythm, and sexual behavior, among others. By observing changes in mouse behavior during testing, conclusions may be derived by researchers as to the effect the drugs/treatments may have on humans.
Use of mice for evaluating the effects of drugs/treatment has led researchers to generate thousands of mutant mouse strains. The researchers generally first identify the genes and mechanisms involved in various human heritable diseases to enable the assessment of potential therapeutic tools. With this information, the researchers generate mutant mouse strains phenotyping each strain and assigning a function to each mouse gene.
In order to behaviorally phenotype a mouse strain, a wide range of experimental set-ups and methodologies are currently required. For example, models of generalized anxiety disorders include approach-avoidance conflict behaviors, including the elevated plus maze, light-dark exploration, open field exploration [1-6]. Detection of memory deficits in Alzheimer's models include using learning and memory tests, including spatial navigation tasks such as the Morris water maze, Barnes maze, radial maze, and T-maze; emotional memory tasks such as contextual and cued fear conditioning; and aversive tasks such as active and passive avoidance [7-10]. Parkinson's and Huntington's disease models include use of sensitive motor tasks such as balance beam walking, walking and footprint pattern (e.g. cat walk system, Noldus) [8, 11-14]. Rodents' tasks sensitive to antidepressant drugs include forced swim, tail suspension, and stressor-induced anhedonia [2, 15-17].
There are few standard possibly automated behavioral paradigms that are routinely used to assay autism-like social behavioral symptoms in mouse models, albeit in very artificial settings, including a three chambered apparatus that is used to assay sociability and social memory, a phenotyper apparatus that scores the social interactions of a resident mouse with an intruding novel mouse, and auditory communication assays that quantify the level of ultrasonic vocalization of new born pups when being separated from their mother [22-24, 26, 27].
Some systems and methods for behaviorally phenotyping mouse strains or for assessing the effects of drugs/treatments on the mice include means for tracking their movements under diverse environments. In some cases, the tracking means may include use of radio frequency identification (RFID) technology with RFID transponders implanted in the mice. The art includes the following:                a) Kritzler et al., An RFID-based Tracking System for Laboratory Mice in a Semi NaturalEnvironment, www(dot)citeseerx(dot)ist(dot)psu(dot)edu/viewdoc/.        b) Kritzler et al., A GIS Framework for Spatio-temporal Analysis and Visualization of Laboratory Mice Tracking Data, www(dot)onlinelibrary(dot)wiley(dot)com/.        c) Kritzler et al., Analysing Movement and Behavioural Patterns of Laboratory Mice in a Semi Natural Environment based on Data collected via RFID-Technology, www(dot)citeseerx(dot)ist(dot)psu(dot)edu.        d) Lewejohann et al., Behavioral phenotyping of a murine model of Alzheimer's disease in a seminaturalistic environment using RFID tracking, www(dot)springerlink(dot)com.        e) Kritzler et al, Concept of a Framework for Moving Objects based on different Data Sources, www(dot)dfki(dot)de/web/forschung/publikationen.        f) U.S. Pat. No. 7,269,516 to Brunner et al, which describes a “A system and method used to assess animal behavior includes a module having sensors that collects a variety of physical and biological data from a test subject.”Additional references include:            1. Crawley, J. N., Exploratory behavior models of anxiety in mice. Neurosci Biobehav Rev, 1985. 9(1): p. 37-44.    2. Crawley, J. N., Behavioral phenotyping of rodents. Comp Med, 2003. 53(2): p. 140-6.    3. File, S. E., Factors controlling measures of anxiety and responses to novelty in the mouse. Behav Brain Res, 2001. 125(1-2): p. 151-7.    4. Holmes, A., et al., Abnormal anxiety-related behavior in serotonin transporter null mutant mice: the influence of genetic background. Genes Brain Behav, 2003. 2(6): p. 365-80.    5. Clement, Y., et al., Anxiety in mice: a principal component analysis study. Neural Plast, 2007. 2007: p. 35457.    6. Clement, Y., F. Calatayud, and C. Belzung, Genetic basis of anxiety-like behaviour: a critical review. Brain Research Bulletin, 2002. 57(1): p. 57-71.    7. Crawley, J. N., Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests. Brain Res, 1999. 835(1): p. 18-26.    8. Crawley, A. C., What's Wrong With My Mouse? Behavioal Phenotyping of Trasgenic and Knockout Mice. 2000, New York: Wily-Liss.    9. Morris, R. G., Episodic-like memory in animals: psychological criteria, neural mechanisms and the value of episodic-like tasks to investigate animal models of neurodegenerative disease. Philos Trans R Soc Lond B Biol Sci, 2001. 356(1413): p. 1453-65.    10. Higgins, G. A. and H. Jacobsen, Transgenic mouse models of Alzheimer's disease: phenotype and application. Behavioural Pharmacology, 2003. 14(5-6): p. 419-38.    11. Carter, R. J., J. Morton, and S. B. Dunnett, Motor coordination and balance in rodents. Curr Protoc Neurosci, 2001. Chapter 8: p. Unit 8 12.    12. Carter, R. J., et al., Characterization of progressive motor deficits in mice transgenic for the human Huntington's disease mutation. J Neurosci, 1999. 19(8): p. 3248-57.    13. Sedelis, M., R. K. Schwarting, and J. P. Huston, Behavioral phenotyping of the MPTP mouse model of Parkinson's disease. Behav Brain Res, 2001. 125(1-2): p. 109-25.    14. Steele, A. D., et al., The power of automated high-resolution behavior analysis revealed by its application to mouse models of Huntington's and prion diseases. Proceedings of the National Academy of Sciences of the United States of America, 2007. 104(6): p. 1983-1988.    15. Markou, A., et al., Removing obstacles in neuroscience drug discovery: the future path for animal models. Neuropsychopharmacology, 2009. 34(1): p. 74-89.    16. Moreau, J. L., Reliable monitoring of hedonic deficits in the chronic mild stress model of depression. Psychopharmacology (Berl), 1997. 134(4): p. 357-8; discussion 371-7.    17. Konkle, A. T., et al., Evaluation of the effects of chronic mild stressors on hedonic and physiological responses: sex and strain compared. Brain Res, 2003. 992(2): p. 227-38.    18. Crawley, J. N., Behavioral phenotyping strategies for mutant mice. Neuron, 2008. 57(6): p. 809-18.    19. Rogers, D. C., et al., Use of SHIRPA and discriminant analysis to characterise marked differences in the behavioural phenotype of six inbred mouse strains. Behav Brain Res, 1999. 105(2): p. 207-17.    20. van der Staay, F. J. and T. Steckler, Behavioural phenotyping of mouse mutants. Behav Brain Res, 2001. 125(1-2): p. 3-12.    21. Ricceri, L., A. Moles, and J. Crawley, Behavioral phenotyping of mouse models of neurodevelopmental disorders: relevant social behavior patterns across the life span. Behav Brain Res, 2007. 176(1): p. 40-52.    22. Silverman, J. L., et al., Behavioural phenotyping assays for mouse models of autism. Nature Reviews Neuroscience, 2010. 11(7): p. 490-502.    23. Crawley, J. N., Mouse behavioral assays relevant to the symptoms of autism. Brain Pathol, 2007. 17(4): p. 448-59.    24. Benson, D. D., et al., Gender-specific transfusion affects tumor-associated neutrophil: macrophage ratios in murine pancreatic adenocarcinoma. J Gastrointest Surg, 2010. 14(10): p. 1560-5.    25. Menalled, L., et al., Systematic behavioral evaluation of Huntington's disease transgenic and knock-in mouse models. Neurobiol Dis, 2009. 35(3): p. 319-36.    26. Moy, S. S., et al., Development of a mouse test for repetitive, restricted behaviors: relevance to autism. Behav Brain Res, 2008. 188(1): p. 178-94.    27. DiCicco-Bloom, E., et al., The developmental neurobiology of autism spectrum disorder. J Neurosci, 2006. 26(26): p. 6897-906.    28. Mandillo, S., et al., Reliability, robustness, and reproducibility in mouse behavioral phenotyping: a cross-laboratory study. Physiological Genomics, 2008. 34(3): p. 243-255.    29. Brown, S. D., P. Chambon, and M. H. de Angelis, EMPReSS: standardized phenotype screens for functional annotation of the mouse genome. Nat Genet, 2005. 37(11): p. 1155.    30. Morgan, H., et al., EuroPhenome: a repository for high-throughput mouse phenotyping data. Nucleic Acids Research, 2010. 38(Database issue): p. D577-85.    31. Jhuang, H., et al., Automated home-cage behavioural phenotyping of mice. Nat Commun, 2010. 1(6): p. doi:10 1038/ncomms1064.    32. A human pheromone? Lancet, 1971. 1(7693): p. 279-80.